Mutations in the Jagged1 (JAG1) gene, which encodes a ligand for a Notch receptor, are responsible for Alagille syndrome (AGS). AGS is a developmental disorder affecting multiple organ systems including liver, heart, eye, face and vertebrae. Human diseases and mouse phenotypes associated mutations in many other members of the Notch pathway have been described. Since zebrafish is an excellent model for vertebrate development, we have isolated and characterized Jagged homologous genes from zebrafish in order to explore their role in developmental diseases like Alagille syndrome. Three jaggeds termed jagged 1, 2 and 3 were isolated and characterized, along with their chromosomal location and expression. Ectopic expression of jagged RNAs leads to a reduction of neurons in mib mutant embryos that are thought to have a deficit in Notch signalling. Positional cloning revealed that the mib is a novel gene in the Notch pathway, which encodes a RING Ubiquitin ligase that is essential for efficient activation of Notch by Delta. It appears to facilitate activation of the Notch receptor by promoting the endocytosis of the Notch ligand, Delta. Antisense oligonucleotides (Morpholino derivatives) generated for Jaggeds 1, 2 and 3 are being used to explore their role in liver development, which may provide a better understanding of the Alagille syndrome.